The phosphoinositide binding Phox Homology domain of Sorting Nexin 18; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX18, like SNX9, contains an N-terminal Src Homology 3 (SH3) domain, a PX domain, and a C-terminal Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature. The PX-BAR structural unit helps determine specific membrane localization. SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596 267 FQCTIDDPTKQTKFKGMKSYISYKLVPTHTQVPVHRRYKHFDWLYARLAEKFPVISVPHLPEKQATGRFEEDFISKRRKG 346
Cdd:cd07286   1 FQCTIDDPTKQTKFKGMKSYISYKLVPSHTGLQVHRRYKHFDWLYARLAEKFPVISVPHIPEKQATGRFEEDFISKRRKG 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 91598596 347 LIWWMNHMASHPVLAQCDVFQHFLTCPsSTDEKAWKQGKRKAEKDEMV 394
Cdd:cd07286  81 LIWWMDHMCSHPVLARCDAFQHFLTCP-STDEKAWKQGKRKAEKDEMV 127

WASP-binding domain of Sorting nexin protein; The C-terminal region of the Sorting nexin group of proteins appears to carry a BAR-like (Bin/amphiphysin/Rvs) domain. This domain is very diverse and the similarities with other BAR domains are few. In the Sorting nexins it is associated with family PX, pfam00787.13, and in combination with PX appears to be necessary to bind WASP along with p85 to form a multimeric signalling complex.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596   377 DEKAWKQGKRKAEKDEMVGANFFLTLsTPPAAALDLQEVESKIDGFKCFTKKMDDSALQLNHTANEFARKQVTGFKKEYQ 456
Cdd:pfam10456   1 DEKEWKTGKRKAEKDELVGAMFFLTI-EIPEPPLDLQEVEQKVEGFKRFTKKMDDSVKQLLTVGNEFWKKCTGPFKKEYQ 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596   457 KVGQSFRGLSQAFELDQQAFSVGLNQAIAFTGDAYDAIGELFAEQPRQDLDPVMDLLALYQGHLANFPDIIHVQKGALTK 536
Cdd:pfam10456  80 KIGSAFQLLSQVFEMDGYVGSSALNEAIAHTGKTYEEIGEVFAEQPKKDLHPLLETLSEYKGLLGNFPDIIHVHKGAIEK 159

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 91598596   537 VKESRRHVEEGKMEVQKADGIQDRCNTISFATLAEIHHFHQIRVRDFKSQMQHFLQQQIIFFQKVTQKLEEALHKYD 613
Cdd:pfam10456 160 VKESDKLVDEGRISQQEADGMRKRCSIMSYALQAEMNHFHSNRIYDFKSVMQTYLEQQILFYQTIAEKLEKALSRYD 236

Src Homology 3 domain of Sorting nexin 18; SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1. It binds FIP5 and is required for apical lumen formation. It may also play a role in axonal elongation. SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX18 also contains BAR and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 91598596   4 RARALYDFKSENPGEISLREHEVLSLCSEQDIEGWLEGINSRGDRGLFPASYVQV 58
Cdd:cd11897   1 RARALYDFRSENPGEISLREHEVLSLCSEQDIEGWLEGVNSRGDRGLFPASYVEV 55

PhoX homologous domain, present in p47phox and p40phox; Eukaryotic domain of unknown function present in phox proteins, PLD isoforms, a PI3K isoform.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596    287 ISYKLVPTHTQVpvHRRYKHFDWLYARLAEKFPVISVPHLPEKQATGR---FEEDFISKRRKGLIWWMNHMASHPVLAQ- 362
Cdd:smart00312  19 IETKTGLEEWTV--SRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGRlnnFSEEFIEKRRRGLEKYLQSLLNHPELINh 96

                   ....*....
gi 91598596    363 CDVFQHFLT 371
Cdd:smart00312  97 SEVVLEFLE 105

Phox homology (PX) domain protein [Intracellular trafficking and secretion / General function prediction only];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596 264 PYPFQCTIDDPTKQTKFKGMKS-YISYKLVpTHTQVP-----------VHRRYKHFDWLYARLAEKFPVISVPHLPEKQ- 330
Cdd:COG5391 128 DYFISSTVSNPQSLTLLVDSRDkHTSYEII-TVTNLPsfqlresrplvVRRRYSDFESLHSILIKLLPLCAIPPLPSKKs 206

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596 331 ----ATGRFEEDFISKRRKGLIWWMNHMASHPVLAQCDVFQHFLTcpSSTDEKAWKQgkrkaekdemvganffLTLSTPP 406
Cdd:COG5391 207 nseyYGDRFSDEFIEERRQSLQNFLRRVSTHPLLSNYKNSKSWES--HSTLLSSFIE----------------NRKSVPT 268

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596 407 AAALDLQEVeskidgfkcfTKKMDDSALQLNHTANEFARKQVTGFKKEYQKVGQsFRGLSQAFELDQQAFSVGLNQAIAF 486
Cdd:COG5391 269 PLSLDLTST----------TQELDMERKELNESTSKAIHNILSIFSLFEKILIQ-LESEEESLTRLLESLNNLLLLVLNF 337

                       250       260       270       280       290       300
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 91598596 487 tgdaydaIGELFAEQPRQDLDPVMDLLALYQGHLANFPDiIHVQKGALTKVKESRRHVEEGKM 549
Cdd:COG5391 338 -------SGVFAKRLEQNQNSILNEGVVQAETLRSSLKE-LLTQLQDEIKSRESLILTDSNLE 392

WASP-binding domain of Sorting nexin protein; The C-terminal region of the Sorting nexin group of proteins appears to carry a BAR-like (Bin/amphiphysin/Rvs) domain. This domain is very diverse and the similarities with other BAR domains are few. In the Sorting nexins it is associated with family PX, pfam00787.13, and in combination with PX appears to be necessary to bind WASP along with p85 to form a multimeric signalling complex.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596   377 DEKAWKQGKRKAEKDEMVGANFFLTLsTPPAAALDLQEVESKIDGFKCFTKKMDDSALQLNHTANEFARKQVTGFKKEYQ 456
Cdd:pfam10456   1 DEKEWKTGKRKAEKDELVGAMFFLTI-EIPEPPLDLQEVEQKVEGFKRFTKKMDDSVKQLLTVGNEFWKKCTGPFKKEYQ 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596   457 KVGQSFRGLSQAFELDQQAFSVGLNQAIAFTGDAYDAIGELFAEQPRQDLDPVMDLLALYQGHLANFPDIIHVQKGALTK 536
Cdd:pfam10456  80 KIGSAFQLLSQVFEMDGYVGSSALNEAIAHTGKTYEEIGEVFAEQPKKDLHPLLETLSEYKGLLGNFPDIIHVHKGAIEK 159

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 91598596   537 VKESRRHVEEGKMEVQKADGIQDRCNTISFATLAEIHHFHQIRVRDFKSQMQHFLQQQIIFFQKVTQKLEEALHKYD 613
Cdd:pfam10456 160 VKESDKLVDEGRISQQEADGMRKRCSIMSYALQAEMNHFHSNRIYDFKSVMQTYLEQQILFYQTIAEKLEKALSRYD 236

The phosphoinositide binding Phox Homology domain of Sorting Nexin 18; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX18, like SNX9, contains an N-terminal Src Homology 3 (SH3) domain, a PX domain, and a C-terminal Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature. The PX-BAR structural unit helps determine specific membrane localization. SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596 267 FQCTIDDPTKQTKFKGMKSYISYKLVPTHTQVPVHRRYKHFDWLYARLAEKFPVISVPHLPEKQATGRFEEDFISKRRKG 346
Cdd:cd07286   1 FQCTIDDPTKQTKFKGMKSYISYKLVPSHTGLQVHRRYKHFDWLYARLAEKFPVISVPHIPEKQATGRFEEDFISKRRKG 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 91598596 347 LIWWMNHMASHPVLAQCDVFQHFLTCPsSTDEKAWKQGKRKAEKDEMV 394
Cdd:cd07286  81 LIWWMDHMCSHPVLARCDAFQHFLTCP-STDEKAWKQGKRKAEKDEMV 127

The phosphoinositide binding Phox Homology domain of Sorting Nexins 9 and 18; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. This subfamily consists of SNX9, SNX18, and similar proteins. They contain an N-terminal Src Homology 3 (SH3) domain, a PX domain, and a C-terminal Bin/Amphiphysin/Rvs (BAR) domain. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis, while SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596 267 FQCTIDDPTKQTKFKGMKSYISYKLVPTHTQVPVHRRYKHFDWLYARLAEKFPVISVPHLPEKQATGRFEEDFISKRRKG 346
Cdd:cd06862   1 YHCTVTNPKKESKFKGLKSFIAYQITPTHTNVTVSRRYKHFDWLYERLVEKYSCIAIPPLPEKQVTGRFEEDFIEKRRER 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 91598596 347 LIWWMNHMASHPVLAQCDVFQHFLTCpssTDEKAWKQGKRKAEKDEMV 394
Cdd:cd06862  81 LELWMNRLARHPVLSQSEVFRHFLTC---TDEKDWKSGKRKAEKDELV 125

The phosphoinositide binding Phox Homology domain of Sorting Nexin 9; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX9, also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It contains an N-terminal Src Homology 3 (SH3) domain, a PX domain, and a C-terminal Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature. The PX-BAR structural unit helps determine specific membrane localization. Through its SH3 domain, SNX9 binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596 267 FQCTIDDPTKQTKFKGMKSYISYKLVPTHTQVPVHRRYKHFDWLYARLAEKFPV-ISVPHLPEKQATGRFEEDFISKRRK 345
Cdd:cd07285   1 FDCVVADPRKGSKMYGLKSYIEYQLTPTNTNRSVNHRYKHFDWLYERLLVKFGLaIPIPSLPDKQVTGRFEEEFIKMRME 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 91598596 346 GLIWWMNHMASHPVLAQCDVFQHFLtcpSSTDEKAWKQGKRKAEKDEMV 394
Cdd:cd07285  81 RLQAWMTRMCRHPVISESEVFQQFL---NFRDEKEWKTGKRKAEKDETV 126

The phosphoinositide binding Phox Homology domain of Sorting Nexins 1 and 2; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. This subfamily consists of SNX1, SNX2, and similar proteins. They harbor a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. Both domains have been shown to determine the specific membrane-targeting of SNX1. SNX1 and SNX2 are components of the retromer complex, a membrane coat multimeric complex required for endosomal retrieval of lysosomal hydrolase receptors to the Golgi. The retromer consists of a cargo-recognition subcomplex and a subcomplex formed by a dimer of sorting nexins (SNX1 and/or SNX2), which ensures effcient cargo sorting by facilitating proper membrane localization of the cargo-recognition subcomplex.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596 267 FQCTIDDPTKQTKfkGMKSYISYKlVPTHTQVP--------VHRRYKHFDWLYARLAEKFPVISVPHLPEKQATGRFEE- 337
Cdd:cd06859   1 FEISVTDPVKVGD--GMSAYVVYR-VTTKTNLPdfkksefsVLRRYSDFLWLYERLVEKYPGRIVPPPPEKQAVGRFKVk 77

                        90       100       110
                ....*....|....*....|....*....|....*
gi 91598596 338 -DFISKRRKGLIWWMNHMASHPVLAQCDVFQHFLT 371
Cdd:cd06859  78 fEFIEKRRAALERFLRRIAAHPVLRKDPDFRLFLE 112

The Phox Homology domain, a phosphoinositide binding module; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to membranes. Proteins containing PX domains interact with PIs and have been implicated in highly diverse functions such as cell signaling, vesicular trafficking, protein sorting, lipid modification, cell polarity and division, activation of T and B cells, and cell survival. Many members of this superfamily bind phosphatidylinositol-3-phosphate (PI3P) but in some cases, other PIs such as PI4P or PI(3,4)P2, among others, are the preferred substrates. In addition to protein-lipid interaction, the PX domain may also be involved in protein-protein interaction, as in the cases of p40phox, p47phox, and some sorting nexins (SNXs). The PX domain is conserved from yeast to humans and is found in more than 100 proteins. The majority of PX domain-containing proteins are SNXs, which play important roles in endosomal sorting.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596 268 QCTIDDPtkQTKFKGMKSYISYKLVPTHTQVP---VHRRYKHFDWLYARLAEKFPVISVPHLPEKQATGRFEEDFISKRR 344
Cdd:cd06093   1 SVSIPDY--EKVKDGGKKYVVYIIEVTTQGGEewtVYRRYSDFEELHEKLKKKFPGVILPPLPPKKLFGNLDPEFIEERR 78

                        90       100
                ....*....|....*....|....*..
gi 91598596 345 KGLIWWMNHMASHPVLAQCDVFQHFLT 371
Cdd:cd06093  79 KQLEQYLQSLLNHPELRNSEELKEFLE 105

The phosphoinositide binding Phox Homology domain of yeast sorting nexin Vps5p; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Vsp5p is the yeast counterpart of human SNX1 and is part of the retromer complex, which functions in the endosome-to-Golgi retrieval of vacuolar protein sorting receptor Vps10p, the Golgi-resident membrane protein A-ALP, and endopeptidase Kex2. The PX domain of Vps5p binds phosphatidylinositol-3-phosphate (PI3P). Similar to SNX1, Vps5p contains a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. Both domains have been shown to determine the specific membrane-targeting of SNX1.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596 267 FQCTIDDPTKQTKFkgMKSYISYkLVPTHTQVP--------VHRRYKHFDWLYARLAEKFPVISVPHLPEKQATGRFEED 338
Cdd:cd06861   1 FEITVGDPHKVGDL--TSAHTVY-TVRTRTTSPnfevssfsVLRRYRDFRWLYRQLQNNHPGVIVPPPPEKQSVGRFDDN 77

                        90       100       110
                ....*....|....*....|....*....|...
gi 91598596 339 FISKRRKGLIWWMNHMASHPVLAQCDVFQHFLT 371
Cdd:cd06861  78 FVEQRRAALEKMLRKIANHPVLQKDPDFRLFLE 110

Src Homology 3 domain of Sorting Nexin 33; SNX33 interacts with Wiskott-Aldrich syndrome protein (WASP) and plays a role in the maintenance of cell shape and cell cycle progression. It modulates the shedding and endocytosis of cellular prion protein (PrP(c)) and amyloid precursor protein (APP). SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX33 also contains BAR and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 91598596   4 RARALYDFKSENPGEISLREHEVLSLCSEQDIEGWLEGINSRGDRGLFPASYVQV 58
Cdd:cd11896   1 KARALYSFQSENKEEINIQENEELVIFSENSLDGWLQGQNSRGETGLFPASYVEI 55

PhoX homologous domain, present in p47phox and p40phox; Eukaryotic domain of unknown function present in phox proteins, PLD isoforms, a PI3K isoform.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596    287 ISYKLVPTHTQVpvHRRYKHFDWLYARLAEKFPVISVPHLPEKQATGR---FEEDFISKRRKGLIWWMNHMASHPVLAQ- 362
Cdd:smart00312  19 IETKTGLEEWTV--SRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGRlnnFSEEFIEKRRRGLEKYLQSLLNHPELINh 96

                   ....*....
gi 91598596    363 CDVFQHFLT 371
Cdd:smart00312  97 SEVVLEFLE 105

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 91598596      4 RARALYDFKSENPGEISLREHEVLSLCSEQDiEGWLEGINSRGDRGLFPASYVQ 57
Cdd:smart00326   4 QVRALYDYTAQDPDELSFKKGDIITVLEKSD-DGWWKGRLGRGKEGLFPSNYVE 56

The phosphoinositide binding Phox Homology domain of Sorting Nexin 30; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. SNX30 harbors a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain, similar to the sorting nexins SNX1-2, SNX4-8, and SNX32. Both domains have been shown to determine the specific membrane-targeting of SNX1. The specific function of SNX30 has yet to be elucidated.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596 270 TIDDPTKQTKfkGMKSYISYKLVPTHTQV-------PVHRRYKHFDWLYARLAEKFPVISVPHLPE----KQATGRFEED 338
Cdd:cd07283   4 TVDDPKKHVC--TMETYITYRVTTKTTRTefdlpeySVRRRYQDFDWLRNKLEESQPTHLIPPLPEkfvvKGVVDRFSEE 81

                        90       100       110
                ....*....|....*....|....*....|...
gi 91598596 339 FISKRRKGLIWWMNHMASHPVLAQCDVFQHFLT 371
Cdd:cd07283  82 FVETRRKALDKFLKRIADHPVLSFNEHFNVFLT 114

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 91598596   4 RARALYDFKSENPGEISLREHEVLSLCSEQDiEGWLEGINSRGDRGLFPASY 55
Cdd:cd00174   1 YARALYDYEAQDDDELSFKKGDIITVLEKDD-DGWWEGELNGGREGLFPANY 51

The phosphoinositide binding Phox Homology domain of Sorting Nexin 4; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX4 is involved in recycling traffic from the sorting endosome (post-Golgi endosome) back to the late Golgi. It shows a similar domain architecture as SNX1-2, among others, containing a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. SNX4 is implicated in the regulation of plasma membrane receptor trafficking and interacts with receptors for EGF, insulin, platelet-derived growth factor and the long form of the leptin receptor.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 91598596 302 RRYKHFDWLYARLAEKFPVISVPHLPEKQA--------TGRFEEDFISKRRKGLIWWMNHMASHPVLAQCDVFQHFLT 371
Cdd:cd06864  50 RRYSEFELLRNYLVVTYPYVIVPPLPEKRAmfmwqklsSDTFDPDFVERRRAGLENFLLRVAGHPELCQDKIFLEFLT 127

The phosphoinositide binding Phox Homology domain of the fungal protein YPT35; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. This subfamily is composed of YPT35 proteins from the fungal subkingdom Dikarya. The PX domain is involved in targeting of proteins to PI-enriched membranes, and may also be involved in protein-protein interaction. The PX domain of YPT35 binds to phosphatidylinositol 3-phosphate (PI3P). It also serves as a protein interaction domain, binding to members of the Yip1p protein family, which localize to the ER and Golgi. YPT35 is mainly associated with endosomes and together with Yip1p proteins, may be involved in a specific function in the endocytic pathway.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596 284 KSYISYKLV-----PTHTQVPVHRRYKHFDWLYARLAEKFP---VISVPHLPEK----QATGRFEEDFISKRRKGLIWWM 351
Cdd:cd07280  20 GAYVVWKITietkdLIGSSIVAYKRYSEFVQLREALLDEFPrhkRNEIPQLPPKvpwyDSRVNLNKAWLEKRRRGLQYFL 99

                        90
                ....*....|....*....
gi 91598596 352 NHMASHPVLAQCDVFQHFL 370
Cdd:cd07280 100 NCVLLNPVFGGSPVVKEFL 118

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase and similar proteins; This subfamily is composed of Rho GTPase activating proteins (GAPs) with similarity to GRAF. Members contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. Although vertebrates harbor four Rho GAPs in the GRAF subfamily including GRAF, GRAF2, GRAF3, and Oligophrenin-1 (OPHN1), only three are included in this model. OPHN1 contains the BAR, PH and GAP domains, but not the C-terminal SH3 domain. GRAF and GRAF2 show GAP activity towards RhoA and Cdc42. GRAF influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase. GRAF2 regulates caspase-activated p21-activated protein kinase-2. The SH3 domain of GRAF and GRAF2 binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 91598596   4 RARALYDFKSENPGEISLREHEVLSLCSEQDIEGWLEGINSrGDRGLFPASYVQ 57
Cdd:cd11882   1 RARALYACKAEDESELSFEPGQIITNVQPSDEPGWLEGTLN-GRTGLIPENYVE 53

Src Homology 3 domain of Sorting nexin 9; Sorting nexin 9 (SNX9), also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization. SNXs are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNX9 also contains BAR and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 91598596   4 RARALYDFKSEnPG--EISLREHEVLSLCSEQDIEGWLEGINSRGDRGLFPASYVQVI 59
Cdd:cd11898   1 KARVLYDFAAE-PGnnELTVKEGEIITVTNPNVGGGWIEAKNSQGERGLVPTDYVEIV 57

First C-terminal Src homology 3 domain of Fungal Actin-binding protein 1; Abp1 is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a central proline-rich region, and a C-terminal SH3 domain (many yeast Abp1 proteins contain two C-terminal SH3 domains). Yeast Abp1 also contains two acidic domains that bind directly to the Arp2/3 complex, which is required to initiate actin polymerization. The SH3 domain of yeast Abp1 binds and localizes the kinases, Ark1p and Prk1p, which facilitate actin patch disassembly following vesicle internalization. It also mediates the localization to the actin patch of the synaptojanin-like protein, Sjl2p, which plays a key role in endocytosis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 91598596   4 RARALYDFKSENPGEISLREHEVLSLCSEQDiEGWLEGINSRGDRGLFPASYVQV 58
Cdd:cd11962   1 RAVVLYDYEKDEDNEIELVEGEIVTNIEMVD-EDWWMGTNSKGESGLFPSNYVEL 54

Src homology 3 domain of an unknown subfamily of proteins with similarity to Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) proteins; PACSINs, also called Synaptic dynamin-associated proteins (Syndapins), act as regulators of cytoskeletal and membrane dynamics. They bind both dynamin and Wiskott-Aldrich syndrome protein (WASP), and may provide direct links between the actin cytoskeletal machinery through WASP and dynamin-dependent endocytosis. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 91598596   4 RARALYDFKSENPGEISLREHEVLSLCSEQDIEGWLEGINSRGDRGLFPASYVQ 57
Cdd:cd11999   3 RVRAVYDYTGQEPDELSFKAGEELLKVEDEDEQGWCKGVTDGGAVGLYPANYVE 56

Src Homology 3 domain of Cdc42-Interacting Protein 4; This subfamily is composed of Cdc42-Interacting Protein 4 (CIP4), Formin Binding Protein 17 (FBP17), FormiN Binding Protein 1-Like (FNBP1L), and similar proteins. CIP4 and FNBP1L are Cdc42 effectors that bind Wiskott-Aldrich syndrome protein (WASP) and function in endocytosis. CIP4 and FBP17 bind to the Fas ligand and may be implicated in the inflammatory response. CIP4 may also play a role in phagocytosis. It functions downstream of Cdc42 in PDGF-dependent actin reorganization and cell migration, and also regulates the activity of PDGFRbeta. It uses Src as a substrate in regulating the invasiveness of breast tumor cells. CIP4 may also play a role in the pathogenesis of Huntington's disease. Members of this subfamily typically contain an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain, a central Cdc42-binding HR1 domain, and a C-terminal SH3 domain. The SH3 domain of CIP4 associates with Gapex-5, a Rab31 GEF. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 91598596   4 RARALYDFKSENPGEISLREHEVLSLCSEQDIEGWLEGINSRGDRGLFPASYVQV 58
Cdd:cd11911   1 TCTALYDFDGTSEGTLSMEEGEILLVLEEDGGDGWTRVRKNNGDEGYVPTSYIEV 55

First Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of FCH and double SH3 domains protein 1 (FCHSD1) and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. They have only been characterized in silico and their functions remain unknown. This group also includes the insect protein, nervous wreck, which acts as a regulator of synaptic growth signaling. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 91598596   7 ALYDFKSENPGEISLREHEVLSLCSEQDIEGWLEGINSRGDRGLFPASYVQ 57
Cdd:cd11761   6 VLYSYEAQRPDELTITEGEELEVIEDGDGDGWVKARNKSGEVGYVPENYLQ 56

Second Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the second SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 91598596   4 RARALYDFKSENPGEISLREHEVLSLCSEQDiEGWLEG-INSRgdRGLFPASYVQV 58
Cdd:cd11782   1 EARAKYNFNADTGVELSFRKGDVITLTRRVD-ENWYEGrIGGR--QGIFPVSYVQV 53

The phosphoinositide binding Phox Homology domain of fungal Sorting Nexins 41 and 42; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. SNX41 and SNX42 (also called Atg20p) form dimers with SNX4, and are required in protein recycling from the sorting endosome (post-Golgi endosome) back to the late Golgi in yeast.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596 275 TKQTKFKGMKSYISYKL-VPTHTqvpVHRRYKHFDWLYARLAEKFPVISVPHLPEKQATGRF---------EEDFISKRR 344
Cdd:cd06867   7 AGKSSEGGSGSYIVYVIrLGGSE---VKRRYSEFESLRKNLTRLYPTLIIPPIPEKHSLKDYakkpskaknDAKIIERRK 83

                        90       100
                ....*....|....*....|....*.
gi 91598596 345 KGLIWWMNHMASHPVLAQCDVFQHFL 370
Cdd:cd06867  84 RMLQRFLNRCLQHPILRNDIVFQKFL 109

The phosphoinositide binding Phox Homology domain of Sorting Nexins 20 and 21; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. This subfamily consists of SNX20, SNX21, and similar proteins. SNX20 interacts with P-Selectin glycoprotein ligand-1 (PSGL-1), a surface-expressed mucin that acts as a ligand for the selectin family of adhesion proteins. It may function in the sorting and cycling of PSGL-1 into endosomes. SNX21, also called SNX-L, is distinctly and highly-expressed in fetal liver and may be involved in protein sorting and degradation during embryonic liver development.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 91598596 282 GMKSYISYKLVPTHTQVP------VHRRYKHFDWLYARLAEKFP-VISVPHLPEKQATGRFEEDFISKRRKGLIWWMNHM 354
Cdd:cd07279  14 GEKKYVVYQLAVVQTGDPdtqpafIERRYSDFLKLYKALRKQHPqLMAKVSFPRKVLMGNFSSELIAERSRAFEQFLGHI 93

                        90
                ....*....|....*....
gi 91598596 355 ASHPVLAQCDVFQHFLTCP 373
Cdd:cd07279  94 LSIPNLRDSKAFLDFLQGP 112

C-terminal Src Homology 3 domain of the Nebulin family of proteins; Nebulin family proteins contain multiple nebulin repeats, and may contain an N-terminal LIM domain and/or a C-terminal SH3 domain. They have molecular weights ranging from 34 to 900 kD, depending on the number of nebulin repeats, and they all bind actin. They are involved in the regulation of actin filament architecture and function as stabilizers and scaffolds for cytoskeletal structures with which they associate, such as long actin filaments or focal adhesions. Nebulin family proteins that contain a C-terminal SH3 domain include the giant filamentous protein nebulin, nebulette, Lasp1, and Lasp2. Lasp2, also called LIM-nebulette, is an alternatively spliced variant of nebulette. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 91598596   4 RARALYDFKSENPGEISLREHEVLSLCSEQDiEGWLEGINSR-GDRGLFPASYVQ 57
Cdd:cd11789   1 RYRAMYDYAAADDDEVSFQEGDVIINVEIID-DGWMEGTVQRtGQSGMLPANYVE 54

First Src Homology 3 domain of Bzz1 and similar domains; Bzz1 (or Bzz1p) is a WASP/Las17-interacting protein involved in endocytosis and trafficking to the vacuole. It physically interacts with type I myosins and functions in the early steps of endocytosis. Together with other proteins, it induces membrane scission in yeast. Bzz1 contains an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), a central coiled-coil, and two C-terminal SH3 domains. This model represents the first C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 91598596   4 RARALYDFKSENPGEISLREHEVLSLCSEQDIEGWLEGINSRGDRGLFPASYVQV 58
Cdd:cd11912   1 TAKVLYDYTASGDDEVSISEGEEVTVLEPDDGSGWTKVRNGSGEEGLVPTSYIEI 55

Src homology 3 domain of ArfGAP with SH3 domain, ankyrin repeat and PH domain containing proteins; ASAPs are Arf GTPase activating proteins (GAPs) and they function in regulating cell growth, migration, and invasion. They contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, ankyrin (ANK) repeats, and a C-terminal SH3 domain. Vertebrates contain at least three members, ASAP1, ASAP2, and ASAP3, but some ASAP3 proteins do not seem to harbor a C-terminal SH3 domain. ASAP1 and ASAP2 show GTPase activating protein (GAP) activity towards Arf1 and Arf5. They do not show GAP activity towards Arf6, but are able to mediate Arf6 signaling by binding stably to GTP-Arf6. ASAP3 is an Arf6-specific GAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 91598596   4 RARALYDFKSENPGEISLREHEVLSLCSEQD---IEGWLEGINSRgdRGLFPASY 55
Cdd:cd11821   1 RVRALYDCQADNDDELTFSEGEIIVVTGEEDdewWEGHIEGDPSR--RGVFPVSF 53